This application is for the competitive renewal of my K05 Award from NIDA. Since joining the faculty in 1987, my laboratory has made significant contributions to an improved understanding of the molecular mechanisms underlying drug addiction. I was supported for 5 years by a NIDA K02 Award, and for the last 5 years by a NIDA K05. This support has played an instrumental role in my career development by reducing my clinical, teaching, and administrative duties. The requested renewal of my K05 Award would make it possible for me to maintain this focus on academic pursuits and thereby further advance my research and educational activities. The proposed program of research involves two areas of study: 1) the role of the cAMP pathway in mediating some of the long-term actions of opiates in the locus coeruleus, and 2) the role of a series of common, biochemical adaptations in mediating some of the long-term actions of cocaine and opiates in the mesolimbic dopamine system. Support from this K05 Award will enable me to focus on several technical advances that will greatly facilitate the ability of relating specific molecular adaptations (caused by chronic drug exposure in one of these discrete brain regions) to specific aspects of behavioral plasticity to drugs of abuse. This will include the further development of several molecular approaches, which involve viral mediated gene transfer and inducible, cell-targeted mutations in mice. With these tools, and several innovations proposed here in the application of these tools, we will increasingly be able to over express or knock out a protein of interest within a defined brain region of adult rats or mice. By avoiding developmental consequences of genetic mutations and restricting them to specific brain regions, these approaches will reduce limitations currently encountered with traditional transgenic and knockout mice. We also will expand our expertise in the use of DNA micro-array technology to identify novel targets of drug action. In addition, we will further develop the use of diverse types of behavioral models of drug abuse and addiction, which will be coupled with the molecular approaches. These experimental approaches, made possible by this K05 Award, promise to reveal new insight into the mechanisms by which repeated drug exposure leads to the behavioral plasticity of drug addiction.